Controlled drug delivery

ABSTRACT

A medical device for placement in a body of a mammal is provided. The medical device comprises (1) a polymeric matrix forming the device and defining a lumen through the device, the matrix comprising polymer macromolecules and defining spaces between the polymer macromolecules; (2) a drug contained within at least some of the spaces of the matrix; and (3) a material contained within at least some of the spaces of the matrix to affect diffusion of the drug out of the polymeric matrix when the medical device is placed in the body of the mammal.

This application is a continuation of co-pending U.S. patent applicationSer. No. 10/209,476, filed Jul. 31, 2002, entitled “Controlled DrugDelivery,” which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

This invention generally relates to medical devices.

BACKGROUND INFORMATION

A drug can be delivered to a patient by a medical device.Drug-delivering devices generally release the drugs too fast or too slowto achieve desired therapeutic effects. The volume of drug released tothe patient can exceed therapeutic, and even toxic, levels for example.Also, when a drug releases immediately from a medical device, additionaldoses of the drug may need to be delivered to the patient.

SUMMARY OF THE INVENTION

The invention relates to controlled delivery of one or more drugs to abody of a patient via a medical device placed in the patient's body. Amedical device, according to the invention, can deliver one or moredrugs over a desired period of time and at a desired level or volume.The invention allows the release of the drug(s) from the device in acontrolled manner, both in terms of the release time and amount. Forexample, a relatively constant and therapeutic level of a drug can bereleased into the body from a device over a relatively long period oftime, whereas other drug-delivering devices cannot achieve such asustained and constant drug release profile.

In one aspect, the invention features a medical device for placement ina human or other mammal. The device comprises a polymeric matrix forming(entirely or partially) the device and defining a lumen through thedevice. The matrix comprises polymer macromolecules and defines spacesbetween the macromolecules. The device also comprises a drug containedwithin at least some of the spaces and a material contained within atleast some of the spaces. The material affects diffusion of the drug outof the matrix when the device is placed in the body.

In one embodiment according to this aspect of the invention, themolecular weight of the material is greater than that of the drug,thereby hindering and prolonging diffusion of the drug out of thematrix. In another embodiment, the material chemically associates withat least the drug such that the drug must disassociate from the materialbefore diffusing out of the matrix. The device can be a ureteral stentor a catheter, for example, and it can be placed entirely or partiallywithin the patient's body.

In another aspect, the invention involves a hydrophobic polymeric matrixfor coating (entirely or partially) a medical device. The polymericmatrix comprises polymer macromolecules and spaces between themacromolecules. A drug and a material are contained within at least someof the spaces, and the material affects diffusion.

In one embodiment according to this other aspect of the invention, themolecular weight of the material is greater than that of the drug,thereby hindering and prolonging diffusion of the drug out of thematrix. In another embodiment, the material chemically associates withat least the drug such that the drug must disassociate from the materialbefore diffusing out of the matrix.

In yet another aspect, the invention relates to a method of drugdelivery. The method comprises placing a device, entirely or partially,into a body of a human or other mammal. The medical device is capable ofdelivering a therapeutic level of a drug to the body at a predeterminedtime after the device is placed into the body. The method also comprisesproviding a second drug to the body prior to the predetermined time todeliver a therapeutic level of the second drug to the body before thepredetermined time. In one embodiment, the medical device comprises apolymeric matrix as described above.

The foregoing and other objects, aspects, features, and advantages ofthe invention will become more apparent from the following descriptionand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are not necessarily to scale, emphasis instead generallybeing placed upon illustrating the principles of the invention.

FIG. 1A shows an exemplary embodiment of a medical device according tothe invention, specifically a ureteral stent.

FIG. 1B is a cross-sectional view of one embodiment of a medical deviceaccording to the invention, taken along line 2-2 of FIG. 1A.

FIGS. 1C-1E are magnified views of the macromolecular structure of thepolymeric matrix of an embodiment of a medical device according to theinvention.

FIG. 2 shows another exemplary embodiment of a medical device accordingto the invention, specifically a tubular member such as a catheter or aportion of a catheter.

FIG. 3 is a cross-sectional view of one embodiment of a polymeric matrixcoating the surface of a tubular medical device (e.g., a ureteral stentor a catheter) according to the invention.

FIG. 4 is a cross-sectional view of one embodiment of a polymeric matrixcoating the surface of a rod-shaped medical device (e.g., a lead wire)according to the invention.

FIG. 5 depicts a container holding a solution of solvent, drug, andmaterial, and it depicts a stage in the manufacture of a medical devicein accordance with the invention.

FIG. 6 is a graphical comparison of the drug release profile for apolymeric matrix containing drug and material according to the inventionversus the drug release profile for a polymeric matrix containing onlydrug.

FIG. 7 is a graphical representation of the sustained therapeutic druglevels achievable by both placing a drug-delivering medical device anddirectly providing a drug.

DESCRIPTION

In accordance with the invention, a medical device can be used as avehicle to deliver one or more drugs to the body of a patient. Aureteral stent, catheter, and/or other medical device can be used todeliver the drug(s) by placing the device entirely or partially in thebody of a patient. By using certain material(s) and drug(s) in apolymeric matrix, the diffusion of the drug(s) out of the matrix can becontrolled in ways previously unachievable. The invention allows, forexample, one or more drugs to be administered to the patient's body overa sustained time (ranging from days to months, for example) and at arelatively constant, and therapeutic, level.

A drug-delivering medical device according to the invention can beformed (entirely or partially) of a polymeric matrix, loaded with thedrug(s) and material(s) that affect the diffusion of the drug(s) out ofthe matrix when the device is placed in the body of a human or othermammal. The device can be a ureteral stent, a catheter, a dialysis tube,a cannula, a urethral stent, a suture, or other medical device designedfor placement (entirely or partially) in the body. A device according tothe invention can alternatively be coated (entirely or partially) withsuch a loaded polymeric matrix. For example, a hydrophobic polymericmatrix can coat all or some portion of a lead wire, a stent, or acatheter.

FIG. 1A shows a ureteral stent 100 that includes two retention endportions 102, a central portion 104, and a lumen 106 extending throughthe length of the stent. A ureteral stent can be used for maintainingthe patency of a patient's ureter to, for example, help drain urine froma kidney to the bladder in patients with ureteral obstruction or injury,or to protect the integrity of the ureter in a variety of medicalprocedures.

FIG. 2 shows a tubular member 220 that includes a tube 222 and a lumen224 extending therethrough. The member 220 can be a portion of acatheter or it can be a urethral stent, for example, and it can beinserted percutaneously or through a natural body opening into a bodycavity, duct, or vessel to allow the passage of a fluid and/or todistend a passageway. Catheters can be used to drain urine from thebladder, to deliver substances and/or remove blood from the vasculature,and to drain an abscessed area, for example. The stent 100, the member220, and various other medical devices can be used to deliver drug(s) toa body, in accordance with the invention. Whatever the specific deviceused to deliver drug(s), the device can be formed (entirely orpartially) of a loaded polymeric matrix and/or it can be coated(entirely or partially) by a loaded polymeric matrix, in accordance withthe invention. The material(s) and drug(s) loaded within the matrixdetermine the diffusion rate and diffusion characteristics of thedrug(s) when the device is placed, entirely or partially, within a bodyof a patient.

The polymeric matrix should be biocompatible with the patient's body.The polymer should possess the ability to withstand conditions of theinner body environment for the desired period of drug delivery. Thepolymer can, in fact, be biodegradable, but the degradation should notinterfere with the desired course of drug release. Moreover, the polymershould be chemically and physically compatible with both the drug(s) andthe material(s) contained therewithin. In addition, the polymer, whetherforming the medical device itself or being a coating on a medical deviceshould allow diffusion of body fluid, drug, and certain material intoand out of the matrix. The polymeric matrix can be either hydrophobic orhydrophilic, and typically is hydrophobic when the loaded matrix is acoating on a medical device.

The polymeric matrix comprises primarily polymer macromolecules withnaturally occurring spaces and voids interspersed throughout thesemacromolecules. These spaces naturally form a series of channels some ofwhich may traverse from the matrix interior to the matrix surface. Thetotal space that these voids encompass typically will be less than 0.1cubic centimeters per gram of polymer. Within these spaces, drug(s) andmaterial(s) reside. In one embodiment, both the drug(s) and material(s)exist together within at least some of the same spaces. The material(s)affect(s) diffusion of the drug out of the matrix when the device isplaced (entirely or partially) within a body. The permeability of thematrix to body fluid and certain particles, in combination with theinternal spaces allow, in part, for the absorption of body fluid(s) intothe matrix and the release of drug(s) out of the matrix. Upon absorptionof body fluid(s), swelling may occur and new spaces may be created,thereby further affecting drug diffusion from the matrix.

FIG. 1B shows a cross-section of the ureteral stent 100 (one example ofa medical device according to the invention) of FIG. 1A taken along line2-2. The ureteral stent is formed of a polymeric matrix 110. The stent100 has an outer surface 107, in contact with body fluids of the mammalin which the device is placed (entirely or partially), and an innersurface 108 defining a lumen 106 passing through the stent 100. Thepolymeric matrix 110 comprises polymer macromolecules and defines spaces120 between the polymer macromolecules. Many of these spaces 120 containat least a drug 125 and another material 130, and many will contain boththe drug 125 and the material 130. The material 130 affects diffusion ofthe drug 125 out of the matrix 110 when the stent 100 is placed in thebody of the patient (a human or other mammal).

FIG. 3 shows a cross-section of a tubular medical device 300 having anouter surface 309 in contact with a hydrophobic polymeric matrix 310that coats the medical device 300 and an inner surface 307 that definesa lumen 305 passing through the device 300. The tubular medical device300 may be a ureteral stent, a catheter, or a medical device designedfor placement, entirely or partially, in the body. The polymeric matrix310 comprises polymer macromolecules and defines spaces 320 between thepolymer macromolecules. Many of these spaces 320 contain at least a drug325 and another material 330, and many will contain both the drug 325and the material 330. The material 330 affects diffusion of the drug 325out of the matrix 310 when the medical device 300 and polymeric matrix310 are placed within the body of the patient (a human or other mammal).

FIG. 4 shows a cross-section of a rod-shaped medical device 400 havingan outer surface 409 in contact with a hydrophobic polymeric matrix 410coating the medical device 400 according to the invention. The medicaldevice 400 may be a lead wire. The polymeric matrix 410 comprisespolymer macromolecules and defines spaces 420 between the polymermacromolecules. Many of these spaces 420 contain at least a drug 425 andanother material 430, and many will contain both the drug 425 and thematerial 430. The material 430 affects diffusion of the drug 425 out ofthe matrix 410 when the medical device 400 and polymeric matrix coating410 are placed within the body of the patient (a human or other mammal).

Various polymers possess the characteristics described above and, thus,are suitable for forming the matrix according to the invention. Thesepolymers include, but are not limited to, acyl substituted celluloseacetates and alkyl derivatives thereof, partially and completelyhydrolyzed alkylene-vinyl acetate copolymers, unplasticized polyvinylchloride, crosslinked homo- and copolymers of polyvinyl acetate,crosslinked polyesters of acrylic and methacrylate, polyvinyl alkylethers, polyvinyl fluoride, silicone, polycarbonate, polyurethane,polyamide, polysulphones, styrene acrylonitrile copolymers, crosslinkedpoly(ethylene oxide), poly (alkylenes), poly(vinyl imidazole),poly(esters), poly(ethylene terephthalate), and chlorosulphonatedpolyolefines. In one embodiment the polymeric matrix comprises ethylenevinyl acetate (EVA), commercially available from DuPont (Elvax 40W).

One or more drug(s) can be contained within the matrix. In general, anydrug or combination of drugs that possess the ability to induce adesired effect within the body in which the device is placed can beused. Drugs that can be used include, but are not limited to,antispasmodic, local anesthetic, and non-steroidal anti-inflammatory(NSAID). In one embodiment, the drug comprises either oxybutyninchloride or ketorolac. Multiple drugs may be incorporated within thematrix, although for simplicity some of this description refers to asingle drug.

The drug may be highly soluble. Highly soluble drugs tend to diffusefrom a drug delivery device significantly faster than desired, and thesecan be controlled with release techniques according to the invention.The invention is applicable to less soluble drugs as well. Theincorporation of certain materials, including, but not limited to, thosethat are either of low molecular weight or biodegradable, may serve toenhance the diffusion rate of less soluble drugs.

While the size and composition of the drug particle(s) are believed toimpact the ability to control the drug diffusion rate out of the matrix,molecular weight is frequently used as a measure of the size of minuteparticles, and thus it is used here to help specify the range of drugparticle size according to the invention. The drug(s) contained withinthe matrix, according to the invention, typically has a molecular weightless than about 1000. Loading, i.e., the quantity, of drug within thematrix varies according to the nature of the drug, the desiredtherapeutic effect, the desired period of drug delivery into the body,the quantity of the matrix, and the release profile of thediffusion-affecting material, among other factors. Drug loading may bebetween about 0.1 to 50 weight percent of the device depending on theabove-identified factors. In one embodiment, drug loading is betweenabout 2 to 20 weight percent of the device.

In addition to the drug(s), one or more other materials can be containedwithin the polymeric matrix. In general, any material or combination ofmaterials that affect diffusion of the drug out of the matrix in adesirable way can be used. The material, generally, is a polymer or abiomaterial that affects drug diffusion based on its physical and/orchemical properties.

The material(s) can be selected based on the material's release profile.The release profile is a profile of the material's ability to affectdrug diffusion out of the matrix over time, potentially determined byempirical analysis. The particle size of the material(s) may be thedefining property for diffusion control and, as such, appropriatematerial(s) can be selected based on the molecular weight. The greaterthe molecular weight of the material(s), the more significantly thematerial will restrict drug diffusion out of the matrix. For example,assuming the drug incorporated within the matrix has a molecular weightof about 1000, the incorporation into the matrix of material(s)possessing a molecular weight of about 20,000 will tend to decrease thedrug diffusion rate to a greater extent than the incorporation ofmaterial(s) possessing a molecular weight of about 2000. In suchinstances, the material(s) may have a molecular weight between about1000 and 100,000. Selecting a material with a lower molecular weightthan that of the drug tends to increase the diffusion rate of the drugout of the matrix. For example, the material can have a molecular weightof less than about 1000 when the drug has a molecular weight of about1000.

The material's ability to associate chemically with the drug and,optionally, the polymeric matrix itself, may also serve as the drugdiffusion-affecting mechanism. Where the incorporated material possessessuch ability, the drug must overcome the barrier of the chemicalassociation between the drug and the material, prior to diffusion of thedrug out of the matrix. Such associations may be van der waals or ionicbonds. These associations are based on the polarity of the material, andalso on the hydrophobic or hydrophilic nature of the material, the drug,and the polymeric matrix.

The material may be either soluble or nonsoluble. The material may alsobe biodegradable or non-biodegradable to achieve desired drug releaseinto the body. Biodegradable material will control drug release for onlythat period, prior to excessive biodegradation, during which it ispresent in sufficient amounts. Biodegradable material can serve toincrease drug diffusion from the matrix.

Loading of the material in the matrix may be between about 0 to 20weight percent of the device depending on the nature of the material,the quantity of the matrix, the release profile of the material, therelease profile of the drug, the desired drug diffusion effect, and thedesired period for drug delivery, among other factors. In oneembodiment, loading of the material is between about 1 to 10 weightpercent of the device.

Suitable materials include, but are not limited to,styrenethylene-butylene-styrene (SIBS), collagen, alginates,carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), dextrin,plasticizers, lipophilic material and other fatty acid salts, poreformers, sugar, glucose, starch, hyaluronic acid (HA), chelating agents,including ethylenediaminetetraacetic acid (EDTA), polyethylene glycol(PEG), polyethylene oxide (PEO), and copolymers thereof. Multiplematerials of varying release profiles may be incorporated within thematrix with the drug(s) to achieve the desired drug release profile.

A variety of methods can be used to manufacture a medical device or acoating according to the invention. For example, extrusion or injectionmolding can be used.

During extrusion, a molten state polymer is forced under high pressurethrough an opening, thus forming a medical device in the shape of theopening's cross-section. Initially, the solid polymer is melted byrotation of a screw and barrel under extreme heat, friction, andpressure. After the resulting molten polymer is forced through apre-shaped die of desired cross-section, the extrudate is cooled eitherthrough immersion within a water bath or by exposure to air.Incorporation of the material(s) and drug(s) may occur prior to theextrusion process through precompounding with the polymer, or may occuras the polymer is melted during the actual extrusion process (Bridge,R., “Polymer Extrusion,” URL:http://www.engr.uconn.edu/cheg/polymer/c256hnp.htm).

Injection molding provides a similar mechanical method to develop themedical device. During this process, an injection unit melts the polymerand subsequently injects the melt into a hollow mold cavity of desiredshape. A ram fed injection molding machine contains a hydraulicallyoperated plunger, first, to spread a thin layer polymer into a heatedregion; second, to converge the polymer melt at a nozzle; and lastly, toinject the melt into the mold. Alternatively, a reciprocation screwinjection molding machine utilizes a hydraulically operated rotatingscrew to melt, mix and pump polymer after which, the screw serves as aplunger to inject the melt into the mold. Material(s) and drug(s) may beincorporated into the medical device by either precompounding both withthe polymer, or alternatively, by addition during the melting process(Harris, L., “Injection Molding,” URL:http://ww.engr.uconn.edu/cheg/polymer/injmold.htm).

In addition, various chemical processes can be used to manufacture thepolymeric matrix. In a process known as imbibing, material(s) anddrug(s) are incorporated into a preexisting polymeric matrix. Thepolymeric matrix is immersed in a solution of desired concentration ofdrug(s), desired concentration of material(s) and appropriate solvent.Toluene, dimethylformamide (DMF) and methyl ethyl ketone (MEK), amongothers, provide effective solvent for the imbibing process. Uponimmersion, the matrix swells as drug(s), material(s) and solventpenetrate into the matrix's network of channels and voids. Subsequently,solvent may be removed through ventilation, thereby entrapping thedrug(s) and material(s) within the matrix.

Referring to FIG. 5, in imbibing, a container 500 holds a solutioncomprising solvent 503, drug 505, and material 507 and pre-formedpolymeric medical devices 510 (e.g., several stents held in place bymandrels 515) are immersed within the solution to allow the drug 505 andthe material 507 to imbibe into the swelling medical devices 510.

Solvent casting provides an alternative chemical method by which tomanufacture the medical device. The desired amount of drug(s),material(s) and matrix polymer are dissolved in an appropriate solvent,e.g. methylene chloride, to form a casting solution. The resultingmixture is then charged into a mold of desired shape. Finally, the moldis dried, usually under vacuum, allowing the matrix polymer torecrystallize and form the device with material(s) and drug(s) containedwithin the interpenetrating spaces.

Applying a polymeric matrix coating to a medical device can involvedipping or spraying. For example, a mixture of solvent, polymer,drug(s), and material(s) can be applied to the medical device by adipping or spraying mechanism. Subsequently, the solvent carrier isevaporated forming a polymeric matrix coating (containing drug(s) andmaterial(s)) on the medical device surface.

Without being bound to any particular theory, it is believed that drugdelivery out of the polymeric matrix operates by diffusion. Drug(s)reside within the spaces between the polymer macromolecules thatcomprise the polymeric matrix. When the matrix is placed in the body ofa human or other mammal, body fluid permeates into the matrix. Swellingof the matrix with body fluid creates new spaces and channels. Bodyfluid carries drug out of the matrix and into the body. Absent propercontrol, the drug will diffuse out of the matrix at its natural rate,often too fast or too slow to achieve desired therapeutic effects. Byincorporating the drug(s) and the other material(s) within the spaces ofthe polymeric matrix, in accordance with the invention, diffusion of thedrug out of the matrix may be enhanced or restricted, as desired.

The material may restrict and prolong drug diffusion out of the matrixbased on its physical and/or chemical properties. FIG. 6 is a graphicalcomparison of the drug release profile of a drug delivery medicaldevice, according to the invention, containing both drug(s) andmaterial(s) versus a drug delivery medical device containing merelydrug(s) and no drug diffusion-affecting additional material(s). Withoutmaterial(s) contained within the matrix, drug(s) may have a rapid burstdrug release that can exceed therapeutic, or even toxic, levels. Withthe other material(s) contained within the matrix, drug diffusion can berestricted and prolonged at a therapeutic level.

The polymeric matrix may contain materials that restrict diffusion basedon the material's size. Without being bound to any particular theory, itis believed that materials that have a molecular weight greater thanthat of the drug physically hinder diffusion of the drug out of thematrix. It is believed that such materials block the spaces and channelswithin the matrix, thereby restricting the drug's ability to diffuse outof the matrix. Materials with larger molecular weights serve as superiorblocking agents, thereby restricting drug diffusion to an even greaterextent.

The polymeric matrix may also contain materials that restrict diffusionof drug out of the matrix by chemically associating with the drug and,potentially, the matrix. The nature of the chemical association may be,but is not limited to, a van der waals or ionic bond. Certain materialsmay be selected based on their ability to form van der waals bonds withthe drug and the matrix. Without wishing to be bound by any particulartheory, it is believed that the van der waals interactions inhibit themobility of the drug, thereby restricting diffusion of the drug out ofthe matrix. Body fluid may interfere with the bonds and promotediffusion of the drug out of the matrix. Ultimately, the recurring cycleof formation and breaking of bonds between the drug, the matrix and thematerial restricts diffusion of drug out of the matrix.

The molecular weight and the relative hydrophobic and/or hydrophilicproperties of the material are important criteria for selection ofmaterial to associate with the drug and the matrix. Materials having thedesired molecular weight and ratio of hydrophilic/hydrophobic groups arecommercially available from Sigma-Aldrich Co. (St. Louis, Mo.)(www.sigma-aldrich.com). Materials with a greater molecular weight willlikely possess larger hydrophilic and/or hydrophobic groups. As thedesired groups increase in size, it is believed that the material willpossess a greater likelihood of chemically associating with the drug andthe matrix. Furthermore, it is believed that as the groups becomelarger, the strength of the material's chemical association with thedrug and the matrix also increase, thereby further restricting diffusionof drug out of the matrix.

In addition, the hydrophobic and/or hydrophilic nature of the materialcan be a relevant criterion for material selection. Hydrophobicmolecules form van der waals bonds with other hydrophobic molecules.Similarly, hydrophilic molecules form van der waals bonds with otherhydrophilic molecules. Accordingly, the material(s) can be selectedbased on the relative hydrophilic and hydrophobic properties of thematerial(s), the drug(s) and, optionally, the matrix. For example, whereboth the drug and the matrix are hydrophobic, a material with morehydrophobic groups can be used so that the material forms van der waalsbonds with both the drug and the matrix. The greater the material'sratio of hydrophobic groups to hydrophilic groups, the greater thelikelihood that bonds will form, and the greater the affect on the drugdiffusion rate will be. Alternatively, where the drug is hydrophilic andthe matrix is hydrophobic, a material with both hydrophobic andhydrophilic groups may be selected such that the material may bond withboth. In accordance with these embodiments, the material may be, but isnot limited to, polyethylene glycol (PEG), polyethylene oxide (PEO), orcopolymers thereof.

Materials may also be chelating agents. Chelating agents also possessthe ability to associate with both the matrix and the drug, therebyrestricting diffusion of the drug out of the matrix. Generally, bondsbetween chelating agents and each of the drug and the matrix arestronger than van der waals bonds. As a result, the use of chelatingagents may have a greater effect on the drug diffusion rate. Thematerial may be the chelating agent ethylenediaminetetraacetic acid(EDTA).

The material(s) may also be selected based on its polarity. Withoutwishing to be bound by any particular theory, it is believed that byincorporating nonpolar material within the polymeric matrix, the entryof body fluid, polar because of its substantial water content, into thematrix is restricted. Furthermore, it is believed that the nonpolarmaterial creates a hydrophobic macroenvironment that shelters the drugfrom the hydrophilic body fluid that is necessary for drug to diffuseout of the matrix.

FIGS. 1C-1E show magnified views of the macromolecular structure of apolymeric matrix 110 containing drug 125 and material 130, according tothe invention. Both the material and the drug reside within the spaces120 between the polymer macromolecules of the polymeric matrix 110. InFIG. 1C, large molecular weight material 130 physically hinders thediffusion of drug 125 out of the polymeric matrix 110. In FIG. 1D,nonpolar material 130 creates a hydrophobic microenvironment thatshelters the drug 125 from hydrophilic body fluid, thereby restrictingdiffusion of the drug 125 out of the polymeric matrix 110. In FIG. 1E, achemical association 140 between the drug 125 and the material 130restricts diffusion of the drug 125 out of the polymeric matrix 110.

Material contained within the spaces of the polymeric matrix mayincrease the diffusion of drug out of the polymeric matrix. The use ofbiodegradable or low molecular weight material may increase the drugdiffusion rate. As the matrix swells with body fluid, biodegradablematerial will biodegrade quickly thereby creating new spaces andchannels and increasing the drug diffusion rate. Similarly, lowmolecular weight material may diffuse out of the matrix prior to thediffusion of drug out of the matrix, opening new spaces and channels,and thereby increasing the drug diffusion rate. Low molecular weightmaterials include, but are not limited to, low molecular weight PEO andPEG, sugar, glucose, dextrin, starch, collagen, alginate and hyaluronicacid (HA).

The polymeric matrix medical device or a medical device coated entirelyor in part with the polymeric matrix coating is placed within the body,possibly within a lumen. By way of example, but not limited to, thedevices may be placed (either entirely or partially) within a bodycavity, duct, or vessel. In one embodiment, the device, e.g. a ureteralstent, is placed within the ureter of the patient. Upon placement, bodyfluid enters the matrix and interacts with the drug(s) and thematerial(s). Subsequently, the drug(s) will diffuse out of the matrix ata rate determined, in part, by the chemical and/or physical propertiesof the material.

Another aspect of the invention is directed toward drug administrationduring the brief period between the placement of a drug delivery devicewithin the body (either entirely or partially) and drug diffusion out ofthe device. Upon placement, drug should diffuse and achieve therapeuticlevels within the body at a predetermined time. By directly providing asecond drug which will achieve therapeutic levels within the body priorto the aforementioned predetermined time, one can effectively provide acontinuous therapeutic dosage of drug. As an example, the drug releaseperiod from a drug delivery ureteral stent may be between 3 to 30 days.Direct instillation of drug, which takes effect about 2 to 24 hoursafter administration, can serve an important complementary role duringthe first few days following placement of the medical device within thebody. The medical device may be a medical device with incorporateddrug(s) and material(s) described above. However, the method of directdrug administration may be used with any drug-delivering medical device.

FIG. 7 shows a graphical representation of this two step method ofproviding a continuous therapeutic level of drug to a patient. Byproviding intravesical drug delivery which achieves a therapeutic druglevel prior to the predetermined time in which the drug released fromthe stent does so, a continuous and prolonged therapeutic level of drugmay be administered to the patient.

The drug may be administered by direct intravesical drug instillation.The drug may also be administered via a ureteral catheter. By way ofexample, the drug may be administered locally, i.e., near the site ofplacement of the medical device. The drug may also be administered atthe distal end of a placed ureteral stent or in the trigone area of thebladder, both of which are considered to be areas of great stentdiscomfort.

The drug administered directly may be either the same or a differentdrug from that incorporated within the placed medical device. Examplesof drugs for use in this embodiment include, but are not limited to,antispasmodic, local anesthetic, nonsteroidal anti-inflammatory (NSAID),other anti-inflammatory drugs, calcium channel blockers, and othersmooth muscle relaxants.

The invention is not to be limited only to the illustrative descriptionprovided herein. Variations, modifications, and other implementations ofwhat is described herein will occur to those of ordinary skill withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A medical device for placement in a body of amammal, comprising: a polymeric matrix forming the device and defining alumen through the device, the matrix comprising polymer macromoleculesand defining spaces between the polymer macromolecules; a drug containedwithin at least some of the spaces of the matrix; and a materialcontained within at least some of the spaces of the matrix to affectdiffusion of the drug out of the polymeric matrix when the medicaldevice is placed in the body of the mammal, wherein each of the material(130) and the drug has a molecular weight, the molecular weight of thedrug being less than the molecular weight of the material, and whereinthe quantity of drug within the matrix is between 0.1 and 50 weightpercent of the device.
 2. The medical device of claim 1 wherein themedical device is a ureteral stent or a catheter.
 3. The medical deviceof claim 1 wherein the polymeric matrix comprises ethylene vinyl acetate(EVA).
 4. The medical device of claim 1 wherein the polymeric matrix ishydrophobic.
 5. The medical device of claim 1 wherein at least some ofthe spaces that contain the drug also contain the material.
 6. Themedical device of claim 1 wherein the drug comprises oxybutynin chlorideor ketorolac.
 7. The medical device of claim 1 wherein the materialcomprises polyethylene glycol (PEG).
 8. The medical device of claim 1wherein the material is biodegradable.
 9. The medical device of claim 1,wherein the material chemically associates with at least the drug suchthat the drug must dissociate from the material before diffusing out ofthe matrix.
 10. The medical device of claim 1, characterized in thatsaid polymeric matrix is coated onto the device.
 11. The medical deviceof claim 10, wherein the medical device is a lead wire.